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Biomedical subjects

J W Geddes

Publications and source records attributed to J W Geddes.

66 records · Page 4Linked to original sources
PubMed1980

Stability of the glutamate content of synaptosomes during their preparation.

The glutamate content of synaptosomal-enriched fractions is stable during the preparation and isolation of the organelles provided that the temperature of the preparation is maintained at 0--2 degrees C and that inorganic ions are not added to the homogenizing and centrifugation media. Consequently, drug-induced in vivo changes in the glutamate content of nerve endings should be reflected by the corresponding changes in glutamate levels of synaptosomes prepared from the brain tissue.

Animals↗
PubMedDate not supplied

Hippocampal damage and cytoskeletal disruption resulting from impaired energy metabolism. Implications for Alzheimer disease.

To determine if impaired energy metabolism might contribute to some aspects of Alzheimer disease (AD), including the vulnerability of the CA1 region of the hippocampal formation and the altered cytoskeleton evident in neurofibrillary tangles, we examined the effects of metabolic poisons on neuronal damage and cytoskeletal disruption in the hippocampal formation. Intrahippocampal injection of 3-nitropropionic acid (3-NP) and malonic acid resulted in neuronal death, particularly in CA1. Cytoskeletal disruption included loss of dendritic MAP2, but sparing of axonal gamma. MK-801 (a noncompetitive NMDA receptor antagonist) did not atentuate the lesions produced by intrahippocampal injection of malonate. MK-801, however, was effective against intrastriatal malonate. Acute systemic 3-NP resulted in neuronal damage and cytoskeletal disruption in the CA1 region of the hippocampal formation, including an extensive loss of MAP2 immuno-reactivity, but sparing of gamma. The neuronal loss in CA1 was delayed as compared to striatum. Chronic intraventricular infusion of 3-NP produced a different pattern of neuronal damage. Loss of gamma-1 immuno-reactivity was observed in CA3 and CA1 s. orients, whereas MAP2 immunostaining was preserved. These results demonstrate that chronic and acute administration of metabolic inhibitors produce distinct patterns of neuronal damage and cytoskeletal disruption. The results further suggest a differential involvement of the NMDA receptor in malonate-induced neuronal damage in striatum as compared to the hippocampus. The pattern of neuronal damage and cytoskeletal disruption observed following acute metabolic impairment resembled some aspects of neurofibrillary pathology in AD, but did not result in gamma hyperphosphorylation.

Alzheimer Disease↗
PubMedDate not supplied

Plasticity, pathology, and Alzheimer's disease.

Much basic data support the notion that growth factors are important in the maintenance and repair of the CNS. Although local increases in growth factors might contribute to aberrant growth and senile plaque formation in Alzheimer's disease (AD), the administration of growth factor inhibitors as a therapeutic intervention would be predicted to decrease the vulnerability of remaining healthy neurons. The administration of neurotrophic agents in AD may help to protect and maintain neurons, and thereby minimize neuronal death and the resultant sprouting response.

Alzheimer Disease↗
PubMedDate not supplied

N-methyl-D-aspartate receptors and Alzheimer's disease.

The results of several studies now suggest that the density of N-methyl-D-aspartate (NMDA) receptors is maintained in many Alzheimer's disease (AD) cases, although loss of these receptors can occur in specific regions as a consequence of severe neuronal loss. Recent findings demonstrate that there are at least two subtypes of the NMDA receptor which are allosterically regulated. To determine the status of the NMDA receptor in AD, studies are required which will examine the activation state of the NMDA receptor and the properties of subtypes in relation to neuronal density and structure.

Alzheimer Disease↗
PubMedDate not supplied

Plasticity in Alzheimer's disease: too much or not enough?

The goal of optimizing restorative sprouting in Alzheimer's disease is based on the premise that sprouting is beneficial and is deficient in AD. The beneficial aspects of neuronal plasticity have been questioned, however, and other studies suggest that some aspects of sprouting may be exaggerated in AD and contribute to the formation of plaques, tangles, and other neuropathological hallmarks of this disorder. Manipulation of the sprouting response may represent a promising treatment strategy in AD, but whether the goal is to augment or impede sprouting may depend upon the extent of the damage and the severity of the disease state.

Aged↗
PubMedDate not supplied

Protein L-isoaspartyl methyltransferase in postmortem brains of aged humans.

The specific activity of protein L-isoaspartyl methyltransferase, an enzyme implicated in the metabolism of damaged, isoaspartate-containing proteins, has been measured in postmortem samples of parietal cortex from 30 individuals (19 with Alzheimer's disease and 11 controls). Methyltransferase specific activity was positively correlated with age at death, increasing by 2.9 pmol/min/mg of protein for every ten years of age (r = .51, p less than 0.005). This correlation was significant in the control and Alzheimer's disease groups alike. Specific activity also appeared to be about 15% higher in females than in age- and diagnosis-matched males (p less than 0.05). No significant differences were observed between age- and sex-matched Alzheimer patients and controls, suggesting that a deficiency in this enzyme is not responsible for the accumulation of abnormal proteins in Alzheimer's disease.

Aged↗
PubMedDate not supplied

Perikaryal accumulation and proteolysis of neurofilament proteins in the post-mortem rat brain.

Investigations of neurofilament alterations in neurodegenerative disorders utilize postmortem human tissues obtained at autopsy. To determine if alterations in the levels or distribution of neurofilament proteins might occur during the interval between death and autopsy, the postmortem cooling curve of the human brain was modeled in Sprague-Dawley rats and neurofilament proteins were examined by immunocytochemistry and immunoblots. One hour after death, enhanced perikaryal immunostaining of NF-M and both phosphorylated and nonphosphorylated NF-H epitopes was observed throughout the hippocampal formation. A greater number of neurons exhibited increased somatic immunostaining 4-h postmortem. In addition, loss of neurofilament protein immunostaining was observed in the neuropil, particularly in the molecular layer of the dentate gyrus. This corresponded with, but lagged behind, the pattern of calpain activation determined using an antibody against calpain-cleaved alpha-spectrin. Immunoblots confirmed the postmortem loss of neurofilament proteins in both triton-soluble and insoluble fractions. These results demonstrate that the levels and localization of neurofilament proteins observed in tissues obtained at autopsy even with short postmortem intervals may not accurately reflect the premortem condition.

Analysis of Variance↗
PubMedDate not supplied

Carboxy terminal of beta-amyloid deposits in aged human, canine, and polar bear brains.

Immunocytochemistry, using antibodies specific for different carboxy termini of beta-amyloid. A beta 40 and A beta 42(43), was used to compare beta-amyloid deposits in aged animal models to nondemented and demented Alzheimer's disease human cases. Aged beagle dogs exhibit diffuse plaques in the absence of neurofibrillary pathology and the aged polar bear brains contain diffuse plaques and PHF-1-positive neurofibrillary tangles. The brains of nondemented human subjects displayed abundant diffuse plaques, whereas the AD cases had both diffuse and mature (cored) neuritic plaques. Diffuse plaques were positively immunostained with an antibody against A beta 42(43) in all examined species, whereas A beta 40 immunopositive mature plaques were observed only in the human brain. Anti-A beta 40 strongly immunolabeled cerebrovascular beta-amyloid deposits in each of the species examined, although some deposits in the polar bear brain were preferentially labeled with anti-A beta 42(43). beta-amyloid deposition was evident in the outer molecular layer of the dentate gyrus in the aged dog, polar bear, and human. Within this layer, A beta 42 was present as diffuse deposits, although these deposits were morphologically distinct in each of the examined animal models. In dogs, A beta 42 was cloud-like in nature; the polar bear demonstrated a more aggregated type of deposition, and the nondemented human displayed well-defined deposits. Alzheimer's disease cases were most frequently marked by neuritic plaques in this region. Taken together, the data indicate that beta-amyloid deposition in aged mammals is similar to the earliest stages observed in human brain. In each species, A beta 42(43) is the initially deposited isoform in diffuse plaques.

Aged↗
PubMedDate not supplied

Age-specific onset of beta-amyloid in beagle brains.

As part of an effort to characterize Alzheimer's disease-like neuropathy in the canine brain we have determined the age of onset of spontaneous beta-amyloid deposition in 103 laboratory-raised beagles. Tissue samples for each subject were obtained from hippocampal and cortical regions and examined for the incidence and density of beta-amyloid deposition after staining with modified Bielschowsky silver stain and immunohistochemistry. Amyloid deposition was characterized as diffuse plaque or cloud-like formation. The diffuse type of beta-amyloid plaque formation predominated in all brain regions examined. A threshold effect of plaque development was observed; no plaques were apparent in dogs before the age of 10 years, while 36% of dogs aged 11.1-12.9, 60% of dogs aged 13.0-15.0, and 73% of dogs aged 15.1-17.8 developed beta-amyloid deposits. Additionally, a significant increase in plaque density was observed with increasing age.

Age of Onset↗
PubMedDate not supplied

Comparison of neuropathologic criteria for the diagnosis of Alzheimer's disease.

The National Institute on Aging and Reagan Institute (NIA-RI) criteria, and other neuropathologic criteria for Alzheimer's disease (AD), were compared with the clinical diagnosis of dementia in a well defined population of Catholic sisters. The 47-participant subset examined in this study were college educated and lacked complicating conditions such as brain infarcts or diffuse Lewy body disease. Sixteen participants had a clinical diagnosis of dementia. The NIA-RI criteria imply a perfect correlation between neuritic plaque (NP) density and neurofibrillary tangle distribution. However, NP density often did not coincide with tangle distribution. As a result, it was not possible to categorize many of the participants using the NIA-RI guidelines. The 'high likelihood' category of the NIA-RI criteria for AD research settings (neocortical Braak stage and frequent neocortical NP) had relatively high specificity (90% of nondemented participants did not meet this criteria). However, only half of the demented participants were in this category. Neuropathologic criteria requiring the presence of neocortical tangles (rather than neocortical Braak stage) had relatively high sensitivity, accounting for 87-94% of participants with dementia, but also included 32-35% of nondemented participants. Criteria based on neocortical NP or senile plaques had 100% sensitivity, but a majority of nondemented participants also met these criteria. The results support consideration of both tangles and NP for the neuropathologic diagnosis of AD, but indicate that refinement of the NIA-RI criteria is necessary. A possible refinement is suggested for further consideration.

Aged↗
PubMedDate not supplied

Elevated phosphocholine and phosphatidylcholine following rat entorhinal cortex lesions.

At early stages of Alzheimer's disease, phosphomonoesters (PMEs) including phosphocholine (P-choline) are present at elevated levels. PMEs also are elevated in the developing brain during the period of neurite extension. To determine if the elevation of PMEs in AD could reflect neuritic sprouting, 31P-NMR was used to examine phospholipid metabolites and membrane phospholipids at various times following unilateral lesions of the entorhinal cortex, a well-defined model of neuritic sprouting. Two to 7 days postlesion, P-choline levels were elevated 48% in the hippocampus ipsilateral to the entorhinal cortex lesion, but not in the contralateral hippocampus or cerebral cortex. P-choline levels declined by day 15, and reached control levels 45 days following the lesion. The lesion-induced elevation in P-choline could result from increased P-choline synthesis via choline kinase, decreased activity of CTP:phosphocholine cytidylyltransferase, or breakdown of phosphatidylcholine (PC). To distinguish between these possibilities, the membrane phospholipids PC and phosphatidylethanolamine (PE) were measured. Both phospholipids were maintained at or above control levels at each of the postlesion time points, arguing against membrane breakdown or decreased PC synthesis contributing to the elevation of P-choline levels. Other alterations included a widespread elevation in inositol phosphate 2 days postlesion, but not at later time points. The alterations in phospholipid metabolites observed in the rat hippocampus following entorhinal cortex lesions closely resemble those observed in the human brain in the early stages of AD.

Animals↗